Abstract The cure rate for acute lymphoblastic leukemia (ALL) currently exceeds 80%, leaving young survivors with 60+ potential years of life. However, these young patients face major hurdles: 1) initial responses to the disease and to treatment include peripheral neuropathy; myopathy; decreased strength, range of motion, and gross and fine motor function; reduced energy expenditure, fitness, bone mineral content, and bone density; and decreased health-related quality of life (HRQL); 2) long-term effects of therapy include persistent fatigue; decreased physical function/fitness; decreased HRQL; obesity; and significant risk of premature chronic illnesses (e.g., diabetes, osteonecrosis, osteoporosis, cardiovascular disease). Patients' muscle strength, endurance, bone density, and HRQL have been improved by short-term physical activity interventions initiated late in treatment, after function has diminished. We propose to inititate an intervention 7-10 days after medical therapy begins and extend it through 2.5 years of treatment. This will be the first such multidisciplinary, randomized, longitudinal trial of a tailored, parent- and child-focused physical activity program for children (ages 5-18.99 years) with newly diagnosed ALL and will test the ability of the intervention to prevent or diminish early physical function limitations and improve HRQL. Secondary aims will evaluate the mediating effects of motivation and affect and the moderating effects of gender, age, income, and parent education. Through 3 post-baseline assessments 8 weeks, 15 weeks, and 135 weeks after the start of chemotherapy, the intervention will be tested for its effect on: 1) physical function outcomes (muscle strength, range of motion, endurance, gross motor skills), bone density and bone mineral content (135 weeks only); and 2) HRQL. This multi-site trial will test the intervention in 208 children with ALL (104 receiving the intervention and 104 receiving a placebo minimal movement standard care strategy). The knowledge generated by this study has the potential to 1) immediately improve current clinical practices for children with ALL, thereby easing their transition through therapy; 2) provide an effective strategy, based in motivation, that will support life-long behavior changes to minimize late effects of ALL therapy; and 3) extend the intervention to other childhood cancers and to other health risk and health protective behaviors that have the potential to modify late effects of childhood cancer therapy.